Enhancement of learning and memory by flavonoids
Lead Research Organisation:
University of Reading
Department Name: Food and Nutritional Sciences
Abstract
Representing one of the most important lifestyle factors, diet can strongly influence the incidence of cardiovascular disease and neurodegenerative diseases and thus a healthy diet is crucial for healthy ageing. Various bioactive constituents of certain foods and beverages, in particular a class of compounds called flavonoids, have generated interest over the last few years. Recent dietary intervention studies, in particular those using wine, tea, cocoa or blueberries, have begun to demonstrate beneficial effects on the function of blood vessels and on mental performance. While such foods and beverages differ greatly in chemical composition, nutrient content and calories per serving, they have in common that they are amongst the major dietary sources of two groups of flavonoids known as anthocyanins and flavanols. Dietary supplementation studies in humans and animal models using foods or extracts rich in these flavonoids have indicated that they possess an ability to enhance memory and learning. It is thought that they may do this by 1) protecting vulnerable brain cells, 2) enhancing existing brain cell function, 3) stimulating brain cell regeneration, or 4) triggering the growth of new brain cells and/or new blood vessels. Building on existing human and animal work conducted in our laboratory, this multidisciplinary study is designed to determine how specific flavonoids may enhance memory and learning by focussing on their potential to stimulate the growth of new neurons and blood vessels, and the molecular events which determine these changes. The study will also provide crucial information on the ability of flavonoid-rich foods to produce improvements in memory and learning in human older adults using both behavioural and state-of-the-art, brain imaging (fMRI) techniques. The outcomes of this proposal have implications for exploiting the potential beneficial health effects of flavonoid components of the diet, particularly with relation to counteracting the decline in human learning and memory which is associated with normal and abnormal ageing. If we are able to determine which flavonoids are the most beneficial, and how and where they work in the brain, this will help us develop future strategies to maximise these dietary agents in our foods, for example, by developing plants or novel functional food products with high levels of specific flavonoids. In addition, specific dietary advice on food consumption will be improved, as will guidelines to prevent the indiscriminate marketing of food supplements on the basis of putative protective effects. The proposal will broaden understanding of the role that diet plays in the prevention of human brain ageing and the enhancement of a range of cognitive abilities (e.g., spatial memory, long-term memory). The study will also provide the background for new and promising preventive treatments for tackling cognitive decline. The results of this study therefore have important implications for an ageing population where an increase in healthy ageing is greatly desired. Moreover, the potential benefits in terms of quality of life are relevant to the population as a whole, as are the potential savings in health care costs.
Technical Summary
Dietary derived flavonoids have been shown to protect against age-related cognitive decline in animals and humans. These beneficial effects have been attributed to their potential to act selectively within neuronal signalling pathways that regulate neuronal viability, morphology, neurogenesis and angiogenesis. This proposal is designed to unravel the mechanisms by which flavonoids and flavonoid-rich foods influence learning and memory in animals and humans. In animal investigations, we will underpin changes in our behavioural measures of learning and memory with state-of-the-art measurements of neuronal morphology, angiogenesis and neurogenesis. This will be achieved via the reconstruction of whole neuron and vessel structure from z-stacks of confocal microscope-captured images (Leica TCS SP2 AOBS) using neuroanatomical analysis (Neurolecida; MBF Bioscience). The cellular and molecular basis of morphological changes will be addressed using: 1) targeted gene arrays for neurogenesis, neurotrophins and receptors; 2) Western immunoblotting of relevant signalling pathways, notably mitogen-activated protein kinase (MAPK), cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF) and downstream pathways involved to de novo protein synthesis (mTOR, Arc.Arg3.1 etc); 3) Immunohistochemical analysis of NMDA and AMPA- receptor density and neurogenesis. We will also perform a randomised, double blind, cross-over human intervention study using a group of healthy older adults. The study will employ an analytically well characterised food containing a defined and standardised amount of flavanols (495mg) and a macro- and micronutrient-matched control that contains a low amount of flavanols (23 mg). The success of this intervention will be assessed through changes in neural activity (BOLD) using a state-of-the-art fMRI scanning technique, as well as by performance on a broad range of cognitive tests and measurements of serum BDNF.
Publications
Cifuentes-Gomez T
(2015)
Factors Affecting the Absorption, Metabolism, and Excretion of Cocoa Flavanols in Humans.
in Journal of agricultural and food chemistry
Corona G
(2013)
Phenolic acid intake, delivered via moderate champagne wine consumption, improves spatial working memory via the modulation of hippocampal and cortical protein expression/activation.
in Antioxidants & redox signaling
Corona G
(2009)
Hydroxytyrosol inhibits the proliferation of human colon adenocarcinoma cells through inhibition of ERK1/2 and cyclin D1.
in Molecular nutrition & food research
Gómez-Alonso S
(2012)
Inhibition of colon adenocarcinoma cell proliferation by flavonols is linked to a G2/M cell cycle block and reduction in cyclin D1 expression
in Food Chemistry
Kean RJ
(2015)
Chronic consumption of flavanone-rich orange juice is associated with cognitive benefits: an 8-wk, randomized, double-blind, placebo-controlled trial in healthy older adults.
in The American journal of clinical nutrition
Lamport DJ
(2015)
The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial.
in Psychopharmacology
Lamport DJ
(2014)
Fruits, vegetables, 100% juices, and cognitive function.
in Nutrition reviews
Macready AL
(2009)
Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies.
in Genes & nutrition
Macready AL
(2010)
Cognitive tests used in chronic adult human randomised controlled trial micronutrient and phytochemical intervention studies.
in Nutrition research reviews
Rendeiro C
(2014)
A role for hippocampal PSA-NCAM and NMDA-NR2B receptor function in flavonoid-induced spatial memory improvements in young rats.
in Neuropharmacology
Description | Representing one of the most important lifestyle factors, diet can strongly influence the incidence of cardiovascular disease and neurodegenerative diseases and thus a healthy diet is crucial for healthy ageing. Various bioactive constituents of certain foods and beverages, in particular a class of compounds called flavonoids, have generated interest over the last few years. Dietary supplementation studies in humans and animal models using foods or extracts rich in these flavonoids have indicated that they possess an ability to enhance memory and learning. Our proposal was designed to build on existing human and animal work conducted in our laboratory to determine how specific flavonoids may enhance memory and learning by focusing on their potential to stimulate the growth of new neurons and blood vessels, and the molecular events which determine these changes. Importantly, our study was the first to investigate the ability of flavonoid-rich foods to induce improvements in memory and learning in human older adults using both behavioural and state-of-the-art, brain-imaging techniques. The major findings of our work were as follows: 1. Acute (1 day) intervention with 495 mg of cocoa flavanols in 63 healthy older individuals (aged over 65 yrs.) led to significant improvements in cognitive function. These benefits were observed in two major domains of cognition affected by ageing and in diseases such as Alzheimer's disease: 'executive function' and 'episodic memory'. Interestingly, cocoa flavanol-induced improvements in these cognitive performances were observed within 2 h of consuming the cocoa. There were no observed changes in cognitive performed when the same individuals consumed the control which contained only 23 mg flavanols. 2. When the same older individuals consumed the high flavanol cocoa for 12 weeks, we also observed significant cognitive improvements. However, these cognitive changes were most obvious in those individuals who were consuming the lowest amounts of flavanols at baseline, i.e. those which consumed around 2-3 portions of fruits and vegetables compared to those who consume between 3-7 portions. 3. Blueberry, in doses equivalent to around 200g in humans, and pure anthocyanins and flavanols promoted significant improvements in spatial working memory in old (18 month) and young (1 month) animals. These behavioural effects were accompanied by the activation of signalling pathways linked to memory in the brain (ERK1/2-CREB1 signalling) and with increased levels of a protein called brain-derived neurotrophic factor (BDNF), a protein which allows the neurons to become 'plastic', an important event in effective memory storage and recall. These changes were proceeded by flavonoid-induced changes in the expression of the BDNF gene in specific areas of the hippocampus, notably those known as CA1, CA3 and DG. 4. Blueberry and pure anthocyanins/flavanols were also found to enhance 'learning' through the activation of similar hippocampal proteins associated with synaptic plasticity and morphology. However, with regards to learning we found that pure anthocyanins were most effective. The outcomes of this proposal have implications for exploiting the potential beneficial health effects of flavonoid components of the diet, particularly with relation to counteracting the decline in human learning and memory, which is associated with normal and abnormal ageing. The data here will help us develop future strategies to maximise these dietary agents in our foods, for example, by developing plants or novel functional food products with high levels of specific flavonoids. Overall, the data broaden our understanding of the role that diet plays in the prevention of human brain ageing and the enhancement of a range of cognitive abilities. The study also provides the background for new and promising preventive treatments for tackling cognitive decline and therefore have important implications for an ageing population where an increase in healthy ageing is greatly desired. Moreover, the potential benefits in terms of quality of life are relevant to the population as a whole, as are the potential savings in health care costs. |
Exploitation Route | Public health messages to increase flavanol intake at population level |
Sectors | Agriculture Food and Drink Education Healthcare Pharmaceuticals and Medical Biotechnology |
Description | Diet and Brain Health |
Geographic Reach | Asia |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Greater underdtanding of the influence of flavonoids and brain health and fruit and vegetable intake and prevention of brain disease. |
Description | Alpro Foundation Grant |
Amount | £150,000 (GBP) |
Organisation | Alpro Foundation |
Sector | Charity/Non Profit |
Country | Belgium |
Start | 02/2010 |
End | 01/2012 |
Description | BBSRC DRINC research grant 2013 |
Amount | £717,105 (GBP) |
Funding ID | BB/L02540X/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2014 |
End | 10/2017 |
Description | European Union 7th Framework research grant |
Amount | £366,000 (GBP) |
Organisation | European Commission |
Department | Seventh Framework Programme (FP7) |
Sector | Public |
Country | European Union (EU) |
Start | 06/2009 |
End | 06/2012 |
Description | Mars Symboscience |
Organisation | Mars Incorporated UK |
Department | Mars Symboscience |
Country | United States |
Sector | Private |
PI Contribution | R&D of new products based on the research |
Collaborator Contribution | Help with the synthesis of physiologically relevant metabolites of flavanols, through the use of their facilities. |
Impact | Manuscript and addtional funding |
Description | The effects of Champagne wine consumption on brain health |
Organisation | Comité Interprofessionnel du Vin de Champagne (CIVIC) |
Country | France |
Sector | Charity/Non Profit |
PI Contribution | Wrote proposals and hosted PhD students |
Collaborator Contribution | Two Partly funded PhD studentships. Further expands the flavonoid/brain and vascular research programme. |
Impact | Partly funded PhD studentship. Further expands the flavonoid/brain research programme. |
Start Year | 2006 |
Description | The effects of flavanols on brain and vascular health |
Organisation | Mars Incorporated UK |
Country | United Kingdom |
Sector | Private |
PI Contribution | Wrote successful grant application and hosted PhD student |
Collaborator Contribution | Supply of research intervention diets for human clinical trial (£60,000). Fully funded PhD studenship (stipend + fees + runing costs). Enhances my groups work in the flavonoid vascular area. |
Impact | Greatly expands the flavonoid brain and vascular research programme. |
Start Year | 2007 |
Description | 3rd International Conference on Polyphenols and Health |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | International conference; 40 min oral presentation Press release and round table discussions. |
Year(s) Of Engagement Activity | 2009 |
Description | 3rd International Congress on Wine and Health |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | International conference; 30 min oral presentation Press release |
Year(s) Of Engagement Activity | 2008 |
Description | 3rd International Congress on Wine and Health |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | International conference; 20 min oral presentation Conference press release and individual interviews. French media interest |
Year(s) Of Engagement Activity | 2008 |
Description | 4th Internation Conference on Polyphenols and Health |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | 45 min Plenary lecture with questions and discussion afterwards, around 20 min Requests for publications and further work with Industry stimulated. |
Year(s) Of Engagement Activity | 2011 |
Description | 5th Internation Conference on Polyphenols and Health |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | 1h Plenary session with round table discussion (1h). Discussion was wide ranging and set targets for research over the next 2-5 years requests for Industry projects and manuscript requests |
Year(s) Of Engagement Activity | 2013 |
Description | Annual Congress Oxidants and Antioxidants in Biology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | International conference; 15 min oral presentation Collaboration |
Year(s) Of Engagement Activity | 2007 |
Description | Diet and Brain Health Film |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Recorded and film for the University of Reading regarding the research area. ~15 min and published on the Universities website Increased recruitment. Increased Industrial funding. |
Year(s) Of Engagement Activity | 2010 |
Description | Fourth European Nutrigenomics Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | European Conference; 20 min oral presentation Press release for conference and media interest |
Year(s) Of Engagement Activity | 2008 |
Description | Mars Nutrition Research Council |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Industrial Conferenece; 40 min oral presentation Funding directed towards this research in 2007, 2008 and 2009. |
Year(s) Of Engagement Activity | 2007 |
Description | Oxygen Club California |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | International conference; 45 min oral presentation Press conference and discussion regarding future research focus in the area. |
Year(s) Of Engagement Activity | 2009 |
Description | Oxygen Club of California |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | International conference; 30 min oral presentation. media interest in the USA |
Year(s) Of Engagement Activity | 2007 |
Description | Royal Pharmaceutical Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | International conference; 45 min oral presentation Press release and media interviews |
Year(s) Of Engagement Activity | 2009 |
Description | Science Museum's Dana Centre |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | public event venue for contemporary science debate. Press conference leading to interviews with The Times, The Observer, The Daily Mail and The Wine Spectator about some of the MRC research outputs. 1h show on Superfoods which aired on BBC2 in August 2007. Interviews with Channel 4 News and BBC radio. The MRC was referred to as funder where possible. |
Year(s) Of Engagement Activity | 2007 |
Description | Scirus Topic Pages |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | Design of website more public awareness of the research area |
Year(s) Of Engagement Activity | 2012 |
Description | Sixth Form Summer School |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | organisation and running of the laboratory sessions as part of the School of Food Biosciences 'Sixth Form Open Day'. This course gives A-level students a chance to experience the academic research environment. Experiments related to this MRC grant were used in order to show how certain nutrients may be beneficial to human brain health. June 2005, 2006, 2007 and 2008 Increased recruitment of students. |
Year(s) Of Engagement Activity |
Description | Society for Free Radical Research-International |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | International conference; 30 min oral presentation Media interest |
Year(s) Of Engagement Activity | 2007 |
Description | TV Programme |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Part of TV programme "Britain's Favourite Supermarket Foods". Filmed a section for this programme on the MRC funded research. Further media interest and school presentations |
Year(s) Of Engagement Activity | 2012 |
Description | TV Programme |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Part of a TV programme 'The Food Hospital". Filmed a piece relating to the MRC funded research. A number of schools have requested lay talks to pupils. |
Year(s) Of Engagement Activity | 2014 |
Description | The Nutrition Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | International conference; 30 min oral presentation Press release and significant media interest. Collaborations made and grants applied for. |
Year(s) Of Engagement Activity | 2008 |
Description | The Times, The Observer, The Daily Mail and The Wine Spectator |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Edited Interviews for publication, mainly 2007 and 2008 Interest from the general public and NHS |
Year(s) Of Engagement Activity | 2009 |
Description | Third European Nutrigenomics Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | European conference; 20 min oral presentation Conference press release and media interest |
Year(s) Of Engagement Activity | 2007 |
Description | Website articles - Various |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Usually telephone interviews followed by publication of edited interview on public websites. Interest from the general public usually by email |
Year(s) Of Engagement Activity |